Fig 4.

Persistence caused by type I toxin-antitoxin systems. (A) Illustration of antibiotic killing kinetics (left) and corresponding bacterial populations (right). Susceptible cells are rapidly killed (gray), while resistant cells continue growing (blue) in the presence of drugs (e.g., bactericidal antibiotics). If persister cells are present, a biphasic killing curve emerges due to long-term antibiotic tolerance of the persister subpopulation (red). (B) Induction of persistence by type I toxins. An active cell has a polarized membrane (as indicated by protons at the outside of its cytoplasmic membrane). The proton gradient is used by ATPases to produce ATP (top middle). Active cells are susceptible and rapidly killed when exposed to drugs (top left). Some type I toxins are pore-forming membrane toxins (red) with the potential to promote a drug-tolerant persister state. Type I toxins may impede drug uptake due to depolarization of the cytoplasmic membrane (upper right). In addition, depolarization inhibits ATP production and leads to ATP depletion (bottom right). Alternatively, type I toxins form pores that are capable of promoting ATP efflux (bottom left). Decreasing ATP levels cause cellular inactivity, which prevents killing by drugs.